Indolinone derivatives and process for their manufacture

ABSTRACT

The present invention relates to specific indolinone derivatives, namely the compounds of formula, in which R 1  represents an hydrogen atom or a group, and R 2  and R 3  each represent an hydrogen atom or R 2  and R 3  taken together represent a group, with the proviso that when R 1  represents an hydrogen atom R 2  and R 3  taken together represent a group, and to a process for their manufacture.

The present invention relates to specific indolinone derivatives, namelythe compounds of formula

-   -   in which R¹ represents an hydrogen atom or a Cl—CH₂—CO-group,        and R² and R³ each represent an hydrogen atom or R² and R³ taken        together represent a

-   -    group,    -   with the proviso that when R¹ represents an hydrogen atom R² and        R³ taken together represent a

-   -    group,        and to a process for their manufacture.

The above mentioned indolinone derivatives are useful intermediates forthe synthesis of drug substances, such as those disclosed for example inthe following patent applications: WO 01/027081, WO 04/013099, WO04/017948, WO 04/096224 and WO 06/067165. These patent applicationsdisclose drug substances and the use of these drug substances or of apharmaceutically acceptable thereof in a pharmaceutical composition totreat oncological or non-oncological diseases via inhibition of theproliferation of target cells, alone or in combination with furthertherapeutic agents. The mechanism of action by which the proliferationof the target cells occurs is essentially a mechanism of inhibition ofseveral tyrosine kinase receptors, and especially an inhibition of thevascular endothelial growth factor receptor (VEGFR).

Although the above-mentioned patent applications already describe aprocess to manufacture the drug substances, an object of the presentinvention is a new and improved process for the manufacture ofintermediates useful for the synthesis of said drug substances. Hence,the process in accordance with the present invention presents amongstothers the following remarkable advantages when compared to theprocesses already described in the prior art.

A first advantage is the higher overall yield which can be obtained viathe new and improved process. This higher overall yield represents animprovement in the overall efficiency of the process. This implies alsoan economic advantage.

A second advantage is that the new and improved process in accordancewith the present invention is more friendly towards the environment thanthe processes already known from the prior art. This advantage is basedon the fact that the process steps are conducted at higherconcentrations.

A third advantage which can be pointed out is the large scale productionappropriateness of the new and improved process in accordance with thepresent invention. This appropriateness is characterized by the presenceof robust reaction steps, i.e. reaction steps which are less sensitiveto the inputs.

These advantages ensure the required high purity of the activepharmaceutical active ingredient.

The process in accordance with the present invention is shown in thefollowing General Synthesis Scheme 1.

The following nomenclature is used throughout the present invention.

Custom name used in present patent application Corresponding IUPAC name“CHLORIMIDE” methyl 1-(chloroacetyl)-2-oxoindoline-6- carboxylate“CHLORENOL” methyl 1-(chloroacetyl)-3- (E or Z isomer)[methoxy(phenyl)methylene]-2-oxoindoline-6- carboxylate “ENOLINDOLE”methyl 3-[methoxy(phenyl)methylene]-2- (E or Z isomer)oxoindoline-6-carboxylate

Thus, in accordance with the present invention, the process comprisesthe following steps.

I. Synthesis of the 6-methoxycarbonyl-2-oxindole

The 6-methoxycarbonyl-2-oxindole may be synthesized in accordance withthe processes shown in following synthesis schemes A or B. Theseprocesses have already been described in the prior art.

-   -   Hence, the 6-methoxycarbonyl-2-oxindole is obtainable by a        three-step procedure consisting of an esterification of        3-nitro-benzoic acid, followed by an electrophilic substitution        using chloroacetic acid methyl ester, leading to        4-methoxycarbonylmethyl-3-nitro-benzoic acid methyl ester, and        to a final hydrogenation-intramolecular amidation sequence.

-   -   The 6-methoxycarbonyl-2-oxindole is also obtainable by the above        four-step procedure. Starting with the chain prolongation of        4-methyl-3-nitro-benzonitrile and reductive cyclisation of the        resulting (4-cyano-2-nitro-phenyl)acetic acid to the oxindole        scaffold, the synthesis is concluded by the saponification of        the nitrile group and the subsequent esterification of the        carboxylic acid functionality.

Alternatively, the 6-methoxycarbonyl-2-oxindole may also be synthesizedin accordance with the process to synthesize 2-oxindoles described inU.S. Pat. No. 6,469,181.

Alternatively, the 6-methoxycarbonyl-2-oxindole may be synthesized inaccordance with the process shown in the following synthesis scheme C.

The steps of this synthesis scheme C, which is also an object of thepresent invention, will be further described in the followingexperimental Example 1, which shall not be construed as a limitation ofthe present invention.

IIa. Reaction of the 6-methoxycarbonyl-2-oxindole with chloroaceticanhydride to obtain the “chlorimide” (methyl1-(chloroacetyl)-2-oxoindoline-6-carboxylate)

The reaction of 6-methoxycarbonyl-2-oxindole with chloroacetic anhydrideor another appropriately activated chloroacetic acid derivative, e.g.chloroacetyl chloride, is preferably carried out in a high boiling andaprotic solvent, for instance toluene, xylene or butyl acetate, at atemperature of about 80° C. to about 130° C.

The crystallisation is initiated by addition of a non-polar solvent, forinstance cyclohexane or methyl cyclohexane, at a temperature of about80° C. to about 100° C., and completed at a temperature of about −5° C.to room temperature. The solid is collected, washed, preferably withpolar solvents such as alcohols, most preferably methanol, and dried, togenerate the “chlorimide” compound.

The alkylating agents such as chloroacetyl chloride or chloroaceticanhydride may be purchased from different sources. A supplier of largeamounts of chloroacetic anhydride is, for example, SF-Chem(Switzerland).

The above reaction step IIa and the product of the reaction, i.e. the“chlorimide” (methyl 1-(chloroacetyl)-2-oxoindoline-6-carboxylate), arealso an object of the present invention.

IIb. Reaction of the “chlorimide” with trimethylorthobenzoate to obtainthe “chlorenol” (methyl1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

The reaction of the methyl 1-(chloroacetyl)-2-oxoindoline-6-carboxylatewith trimethylorthobenzoate is carried out in a high boiling and aproticsolvent such as butyl acetate, N,N-dimethylformamide, xylene orpreferably toluene, at temperatures of about 100° C. to about 140° C.The reaction is mediated by methanol scavengers such as aceticanhydride. In the course of the reaction, volatile parts can bedistilled off with or without replacement of the removed parts by thereaction solvent. The crystallisation is finished at ambient temperatureto about −10° C. The solid is collected and washed, preferably withsolvents such as toluene, xylene and/or ethyl acetate. After drying, the“chlorenol” compound is obtained.

Acetic anhydride may be purchased from different sources.

Trimethylorthobenzoate may be purchased from AMI Drugs & SpecialityChemicals India Inc.

The above reaction step IIb and the product of the reaction, i.e. the“chlorenol” (methyl1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate),are also an object of the present invention.

IIc. Reaction of the “chlorenol” with bases to obtain the “enolindole”(methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

The base catalyzed dechloroacetylation ofmethyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylateis carried out in protic solvents such as alcohols, e.g. isopropanol orpreferably methanol, at temperatures of about 70° C. to ambienttemperature. Inorganic bases such as alkali hydroxides or organic basessuch as sodium methoxide may be used as catalysts. The crystallisationis finished at ambient temperature to about −10° C. The solid iscollected and washed, preferably with alcohols, most preferablymethanol. After drying, the “enolindole” compound is obtained.

The above reaction step IIc and the product of the reaction, i.e. the“enolindole”(methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate), arealso an object of the present invention.

A first object of the present invention is thus a compound of formula

-   -   in which R¹ represents an hydrogen atom or a Cl—CH₂—CO-group,        and R² and R³ each represent an hydrogen atom or R² and R³ taken        together represent a

-   -    group,    -   with the proviso that when R¹ represents an hydrogen atom R² and        R³ taken together represent a

-   -    group.

A further object of the present invention is the compound of formula

A further object of the present invention is the compound of formula

A further object of the present invention is the compound of formula

A further object of the present invention is the following process D forthe manufacture of a compound of formula

which comprises the step of base catalyzed dechloroacetylation of acompound of formula

A further object of the present invention is the following process D1,based on the above process D, and in which the compound of formula

is obtained by reacting a compound of formula

with a compound of formula

A further object of the present invention is the following process D2,based on the above process D1, and in which the compound of formula

is obtained by reacting a compound of formula

with a compound of formula

A further object of the present invention is the following process D3,based on the above processes D2, and in which the compound of formula

is obtained by the following steps:

-   -   (i) esterification of a compound of formula

-   -    to obtain a compound of formula

-   -   (ii) reacting the product of the reaction (i) with malonic acid        dimethylester, to obtain a compound of formula

-   -   (iii) performing a cyclisation of the product of the        reaction (ii) by a reaction of hydrogenation.

A further object of the present invention is a process for themanufacture of a compound of formula

comprising the step of reacting a compound of formula

with a compound of formula

A further object of the present invention is a process for themanufacture of a compound of formula

comprising the step of reacting a compound of formula

with a compound of formula

The present invention will be described in more details in the followingby way of examples, which are illustrative of further embodiments andshall not construe a limitation of the invention.

In the following examples, the synthesis of the drug substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,disclosed in WO 01/027081, WO 04/013099, WO 04/017948, WO 04/096224 andWO 06/067165, is described.

This synthesis is performed in accordance with the following GeneralSynthesis Scheme 2.

In the above General Synthesis Scheme 2 and in the following Examples,the following nomenclature is used.

Custom name Corresponding used in present chemical name used patent inpresent patent application application Corresponding IUPAC name“CHLORIMIDE” methyl 1-(chloroacetyl)-2- oxoindoline-6-carboxylate“CHLORENOL” methyl 1-(chloroacetyl)-3- (E or Z isomer)[methoxy(phenyl)methylene]-2- oxoindoline-6-carboxylate “CHLOROACETYL”chloracetyl-N-methyl-4- N-(4-nitroanilino)-N-methyl-2-chloro-nitroaniline acetamide “NITROANILINE” N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide “ANILINE”N-(4-aminophenyl)-N-methyl-2-(4- methylpiperazin-1-yl)acetamide“ENOLINDOLE” methyl 3- (E or Z isomer) [methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate “ANILINO” 3-Z-[1-(4-(N-((4-methyl- methyl(3Z)-3-[[(4-{methyl[(4- piperazin-1-yl)- methylpiperazin-1-methylcarbonyl)-N- yl)acetyl]amino}phenyl)amino](phenyl)methylene]-methyl-amino)-anilino)- 2-oxoindoline-6- 1-phenyl-methylene]-6-carboxylate methoxycarbonyl-2- indolinone

Example 1 Synthesis of the 6-methoxycarbonyl-2-oxindole in accordancewith the process shown in synthesis scheme C Synthesis of benzoic acid,4-chloro-3-nitro-, methylester

-   -   20 kg of 4-chloro-3-nitro-benzoic acid (99.22 mol) is suspended        in 76 L methanol. 5.9 kg thionylchloride (49.62 mol) is added        within 15 minutes and refluxed for about 3 hours. After cooling        to about 5° C., the product is isolated by centrifugation and        drying at 45° C.

Yield: 19.0 kg (88.8% of theoretical amount)

Purity (HPLC): 99.8%

Synthesis of propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-,dimethylester

-   -   12.87 kg of malonic acid, dimethylester (97.41 mol) is added to        a hot solution (75° C.) of 10.73 kg sodium-tert.amylate (97.41        mol) in 35 L 1-methyl-2-pyrrolidinone (NMP). A solution of 10 kg        benzoic acid, 4-chloro-3-nitro-, methylester (46.38 mol) in 25 L        1-methyl-2-pyrrolidinone is added at 75° C. After stirring for        1.5 hours at about 75° C. and cooling to 20° C., the mixture is        acidified with 100 L diluted hydrochloric acid to pH 1. After        stirring for 1.5 hours at about 5° C., the product is isolated        by centrifugation and drying at 40° C.

Yield: 13.78 kg (95.4% of theoretical amount)

Purity (HPLC): 99.9%

Synthesis of 6-methoxycarbonyl-2-oxindole

-   -   A solution of 13 kg propanedioic acid,        [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester (41.77 mol)        in 88 L acetic acid is hydrogenated at 45° C. and under 40-50        psi in the presence of 1.3 kg Pd/C 10%. After standstill of the        hydrogenation, the reaction is heated up to 115° C. for 2 hours.        The catalyst is filtered off and 180 L water is added at about        50° C. The product is isolated after cooling to 5° C.,        centrifugation and drying at 50° C.

Yield: 6.96 kg (87.2% of theoretical amount)

Purity (HPLC): 99.8%

Example 2 Synthesis of the “chlorimide”(methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate)

Method 1

6-methoxycarbonyl-2-oxindole (400 g; 2.071 mol) is suspended in toluene(1200 ml) at room temperature. Chloroacetic anhydride (540 g; 3.095 mol)is added to this suspension. The mixture is heated to reflux for 3 h,then cooled to 80° C. and methyl cyclohexane (600 ml) is added within 30min. The resulting suspension is further cooled down to room temperaturewithin 60 min. The mother liquor is separated and the solid is washedwith ice cold methanol (400 ml). The crystals are dried to afford 515.5g (93.5%) of the “chlorimide” compound as a white solid. ¹H-NMR (500MHz, DMSO-d₆) δ: 8.66 (s, 1H, 6-H); 7.86 (d, J=8.3 Hz, 1H, 8-H); 7.52(d, J=8.3 Hz, 1H, 9-H); 4.98 (5, 2H, 15-H₂); 3.95 (s, 3H, 18-H₃); 3.88(s, 2H, 3-H₂). ¹³C-NMR (126 MHz, DMSO-d₆) δ: 174.7 (C-2); 36.0 (C-3);131.0 (C-4); 140.8 (C-5); 115.7 (C-6); 128.9 (C-7); 126.1 (C-8); 124.6(C-9); 166.6 (C-10); 165.8 (C-13); 46.1 (C-15); 52.3 (C-18). MS: m/z 268(M+H)⁺. Anal. calcd. for C₁₂H₁₀ClNO₄: C, 53.85; H, 3.77; Cl, 13.25; N,5.23. Found: C, 52.18; H, 3.64; Cl, 12.89; N, 5.00.

Method 2

6-methoxycarbonyl-2-oxindole (10 g; 0.052 mol) is suspended in n-butylacetate (25 ml) at room temperature. To this suspension a solution ofchloroacetic anhydride (12.8 g; 0.037 mol) in n-butyl acetate (25 ml) isadded within 3 min. The mixture is heated to reflux for 2 h, then cooledto 85° C. and methyl cyclohexane (20 ml) is added. The resultingsuspension is further cooled down to room temperature and stirred for anadditional 2 h. The mother liquor is separated and the solid is washedwith methanol (400 ml) at ambient temperature. The crystals are dried toafford 12.7 g (91.5%) of the “chlorimide” compound as a slightly yellowsolid.

Example 3 Synthesis of the “chlorenol”(methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Method 1

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol)is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride(16.2 g; 0.157 mol) is added to this suspension. The mixture is heatedto not less than 104° C. and trimethyl orthobenzoate (20.0 g; 0.108 mol)is added within 60 min. During the addition period and subsequentstirring at the same temperature for 3 h, volatile parts of the reactionmixture are distilled off. The concentration of the reaction mixture iskept constant by replacement of the distilled part by toluene (40 ml).The mixture is cooled down to 5° C., stirred for an additional 1 h andfiltrated. The solid is subsequently washed with toluene (14 ml) andwith a mixture of toluene (8 ml) and ethyl acetate (8 ml). After drying,16.3 g (91.7%) of the “chlorenol” compound are isolated as slightlyyellow crystals. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.73 (d, J=1.5 Hz, 1H,6-H); 8.09 (d, J=8.0 Hz, 1H, 9-H); 7.90 (dd, J=8.1; 1.5 Hz, 1H, 8-H);7.61-7.48 (m, 5H, 21-H, 22-H, 23-H, 24-H, 25-H); 4.85 (s, 2H, 18-H₂);3.89 (s, 3H, 27-H₃); 3.78 (s, 3H, 15-H₃). ¹³C-NMR (126 MHz, DMSO-d₆) δ:165.9 (C-2+C16); 103.9 (C-3); 127.4; 128.6; 130.0; 135.4(C-4+C-5+C-7+C-20); 115.1 (C-6); 126.1 (C-8); 122.5 (C-9); 166.7 (C-10);173.4 (C-13); 58.4 (C-15); 46.4 (C-18); 128.6 (C-21+C-22+C-24+C-25);130.5 (C-23); 52.2 (C-27). MS: m/z 386 (M+H)⁺. Anal. calcd. forC₂₀H₁₆ClNO₅: C, 62.27; H, 4.18; Cl, 9.19; N, 3.63. Found: C, 62.21; H,4.03; Cl, 8.99; N, 3.52.

Method 2

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol)is suspended in xylene (60 ml) at ambient temperature. Acetic anhydride(16.2 g; 0.157 mol) is added to this suspension. The mixture is heatedto reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within40 min and heating is maintained for an additional 4 h. The mixture iscooled down to 0° C. and the mother liquor is separated. The solid issubsequently washed with xylene (14 ml) and a mixture of xylene (8 ml)and ethyl acetate (8 ml). After drying 14.3 g (81.0%) of the “chlorenol”compound are isolated as yellow crystals.

Method 3

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol)is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride(16.2 g; 0.157 mol) is added to this suspension. The mixture is heatedto reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within40 min and heating is maintained for an additional 3 h. The mixture iscooled down to 0° C. and the mother liquor is separated. The solid issubsequently washed with toluene (14 ml) and a mixture of toluene (8 ml)and ethyl acetate (8 ml). After drying 15.3 g (87.3%) of the “chlorenol”compound are isolated as fawn crystals.

Example 4 Synthesis of the “enolindole”(methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Method 1

A solution of potassium hydroxide (0.41 g, 0.006 mol) in methanol (4 ml)is added at 63° C. to a suspension ofmethyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate(8.0 g; 0.020 mol) in methanol (32 ml) C. The mixture is then stirredfor 30 min, cooled to 0° C. and stirring is maintained for 2 h. Afterfiltration, the solid is washed with methanol (24 ml) and dried toafford 6.0 g (94.6%) of the “enolindole” compound as yellow crystals.¹H-NMR (500 MHz, CDCl₃) δ: 8.08 (s, 1H, 1-H); 7.88 (d, J=7.8 Hz, 1H,9-H); 7.75 (m, 1H, 8-H); 7.52-7.56 (m, 3H, 18-H, 19-H, 20-H); 7.40-7.45(m, 3H, 6-H, 17-H, 21-H); 3.92 (s, 3H, 23-H₃); 3.74 (s, 3H, 13-H₃).¹³C-NMR (126 MHz, CDCl₃) δ: 168.8 (C-2); 107.4 (C-3); 130.8 (C-4); 138.2(C-5); 109.4 (C-6); 128.2 and 128.3 (C-7, C-16); 123.5 (C-8); 123.1(C-9); 170.1 (C-11); 57.6 (C-13); 167.2 (C-14); 128.7 and 128.9 (C-17,C-18, C-20, C-21); 130.5 (C-19); 52.1 (C-23). MS (m/z): 310 (M+H)⁺.Anal. calcd. for C₁₈H₁₅NO₄: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.34;H, 4.92; N, 4.56.

Method 2

A suspension ofmethyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate(7.0 g; 0.018 mol) in methanol (28 ml) is heated to reflux. Within 3min, a solution of sodium methoxide in methanol (0.24 g, 30 (w/w), 0.001mol) is added to this suspension. The mixture is then stirred for 30min, cooled to 5° C. and stirring is maintained for 2 h. Afterfiltration, the solid is washed with methanol (9 ml) and dried to afford5.4 g (89.7%) of the “enolindole” compound as yellow crystals.

Method 3

A suspension ofmethyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate(8.0 g; 0.021 mol) in methanol (32 ml) is heated to reflux. A solutionof sodium methoxide in methanol (0.74 g, 30% (w/w), 0.004 mol), furtherdiluted with methanol (4 ml), is added dropwise to this suspension. Themixture is then stirred for 90 min, cooled to 0° C. and stirring ismaintained for 2 h. After filtration, the solid is washed with methanol(24 ml) and dried to afford 5.9 g (91.2%) of the “enolindole” compoundas yellow crystals.

Example 5 Synthesis of the “chloroacetyl”(N-(4-nitroanilino)-N-methyl-2-chloro-acetamide)

Method 1

A suspension of N-methyl-4-nitroaniline (140 g; 0.920 mol) in ethylacetate (400 ml) is heated to 70° C. Within 90 min, chloroacetylchloride (114 g; 1.009 mol) is added to this suspension. Theresulting solution is then refluxed for 1 h, cooled to 60° C. and methylcyclohexane (245 ml) is added. The suspension is further cooled down to0° C. and stirred for an additional 1 h. The reaction mixture isfiltrated, washed with methyl cyclohexane (285 ml) and the precipitateis dried to afford 210.4 g (92.7%) of the “chloroacetyl” compound aswhite crystals. ¹H-NMR (500 MHz, DMSO-d₆) δ: 8.29 (d, J=8.5 Hz, 2H,1-H+3-H); 7.69 (d, J=8.5 Hz, 2H, 4-H+6-H); 4.35 (s, 2H, 9-H₂); 3.33 (s,3H, 12-H₃). ¹³C-NMR (126 MHz, DMSO-d₆) δ: 124.6 (C-1+C-3); 145.6 (C-2);127.4 (C-4+C-6); 148.6 (C-5); 165.6 (C-8); 42.7 (C-9); 37.2 (C-12). MS(m/z): 229 (M+H)⁺. Anal. calcd. for C₉H₉ClN₂O₃: C, 47.28; H, 3.97; N,12.25. Found: C, 47.26; H, 3.99; Cl, 15.73; N, 12.29.

Method 2

A suspension of N-methyl-4-nitroaniline (20.0 g; 0.131 mol) in ethylacetate (20 ml) is heated to 60° C. Within 15 min, a solution of chloroacetic anhydride (26.0 g; 0.151 mol) in ethyl acetate (60 ml) is addedto this suspension. The resulting solution is then refluxed for 1 h,cooled to 75° C. and methyl cyclohexane (80 ml) is added. After seedingat 60° C., the suspension is further cooled down to 0° C. and stirredfor an additional 1 h. The reaction mixture is filtrated, washed withmethyl cyclohexane (40 ml) and the precipitate is dried to afford 25.9 g(83.3%) of the “chloroacetyl” compound as grey crystals.

Example 6 Synthesis of the “nitroaniline”(N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide) and ofthe “aniline”(N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide)

Method 1

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (20.0 g;0.087 mol) in toluene (110 ml) is heated to 40° C. Within 30 min,1-methylpiperazine (21.9 g; 0.216 mol) is added dropwise. After purgingof the dropping funnel with toluene (5 ml) the reaction mixture isstirred for 2 h at 55° C., cooled to ambient temperature and washed withwater (15 ml). The organic layer is diluted with isopropanol (100 ml)and Pd/C (10%; 1.0 g) is added. After subsequent hydrogenation (H₂, 4bar) at 20° C. the catalyst is removed. Approximately ⅘ of the volume ofthe resulting solution is evaporated at 50° C. The remaining residue isdissolved in ethyl acetate (20 ml) and toluene (147 ml) heated to 80°C., then cooled to 55° C. and seeded. The reaction mixture is furthercooled to 0° C. and stirred for 3 h at the same temperature. Afterfiltration, the solid is washed with ice cold toluene (40 ml) and driedto afford 20.2 g (88.0%) of the “aniline” compound as white crystals.

¹H-NMR (500 MHz, DMSO-d₆) δ: 6.90 (d, J=8.5 Hz, 2H, 4-H+6-H); 6.65 (d,J=8.5 Hz, 2H, 1-H+3-H); 5.22 (2H, 19-H₂); 3.04 (s, 3H, 9-H₃); 2.79 (s,2H, 11-H₂); 2.32 (m, 4H, 13-H₂+17-H₂); 2.23 (m, 4H, 14-H₂+16-H₂); 2.10(s, 3H, 18-H₃). ¹³C-NMR (126 MHz, DMSO-d₆) δ: 114.0 (C-1+C-3); 148.0(C-2); 127.6 (C-4+C-6); 131.5 (C-5); 168.9 (C-8); 36.9 (C-9); 58.5(C-11); 52.4 (C-13+C-17); 54.6 (C-14+C-16); 45.7 (C-18). MS (m/z): 263(M+H)⁺. Anal. calcd. for C₁₄H₂₂N₄O: C, 64.09; H, 8.45; N, 21.36. Found:C, 64.05; H, 8.43; N, 21.39.

Method 2

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (14.5 g;0.063 mol) in ethyl acetate (65 ml) is heated to 40° C. Within 30 min,1-methylpiperazine (15.8 g; 0.156 mol) is added dropwise. After purgingof the dropping funnel with ethyl acetate (7 ml) the reaction mixture isstirred at 50° C. for 90 min, cooled to ambient temperature and washedwith water (7 ml). The organic layer is diluted with isopropanol (75 ml)and dried over sodium sulphate. After separation of the solid, Pd/C(10%; 2.0 g) is added and the solution is hydrogenated (H₂, 5 bar) atambient temperature without cooling. Subsequently the catalyst isremoved by filtration and the solvent is evaporated at 60° C. Theremaining residue is dissolved in ethyl acetate (250 ml) andrecrystallized. After filtration and drying 10.4 g (60.4%) of the“aniline” compound are isolated as white crystals.

Example 7 Synthesis of the “anilino”(3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)

Method 1

A suspension ofmethyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g;0.032 mol) andN-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g;0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide(18 ml) is heated to reflux. After 7 h of refluxing the suspension iscooled down to 0° C. and stirring is maintained for additional 2 h. Thesolid is filtered, washed with methanol (40 ml) and dried to afford 15.4g (88.1%) of the “anilino” compound as yellow crystals. ¹H-NMR (500 MHz,DMSO-d₆) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H,33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H,31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H,27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H,15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H₃); 3.06 (m,3H, 12-H₃); 2.70 (m, 2H, 8-H₂); 2.19 (m, 8H, 2-H₂, 3-H₂, 5-H₂, 6-H₂);2.11 (s, 3H, 7-H₃). ¹³C-NMR (126 MHz, DMSO-d₆) δ: 54.5 (C-2+C-6); 52.2(C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1(C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3(C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2(C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4(C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40).MS (m/z): 540 (M+H)⁺. Anal. calcd. for O₃₁H₃₃N₅O₄: C, 69.00; H, 6.16; N,12.98. Found: C, 68.05; H, 6.21; N, 12.81.

Method 2

A suspension ofmethyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g;0.064 mol) andN-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g;0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. Theresulting suspension is cooled down to 10° C. within 1 h and stirring ismaintained for an additional 1 h. After filtration, the solid is washedwith ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the“anilino” compound as yellow crystals.

1. A compound of formula

in which R¹ represents an hydrogen atom or a C₁—CH₂—CO-group, and R² andR³ each represent an hydrogen atom or R² and R³ taken together representa

 group, with the proviso that when R¹ represents an hydrogen atom R² andR³ taken together represent a

 group.
 2. A compound of formula


3. A compound of formula


4. A compound of formula


5. Process for the manufacture of a compound of formula

which comprises the step of base catalyzed dechloroacetylation of acompound of formula


6. Process in accordance with claim 5, in which the compound of formula

is obtained by reacting a compound of formula

with a compound of formula


7. Process in accordance with claim 6, in which the compound of formula

is obtained by reacting a compound of formula

with a compound of formula


8. Process in accordance with claim 7, in which the compound of formula

is obtained by the following steps: (i) esterification of a compound offormula

 to obtain a compound of formula

(ii) reacting the product of the reaction (i) with malonic aciddimethylester, to obtain a compound of formula

(iii) performing a cyclisation of the product of the reaction (ii) by areaction of hydrogenation.
 9. Process for the manufacture of a compoundof formula

comprising the step of reacting a compound of formula

with a compound of formula


10. Process for the manufacture of a compound of formula

comprising the step of reacting a compound of formula

with a compound of formula